Liposomal mitigation of drug-induced long qt syndrome and potassium delayed-rectifier current

ABSTRACT

Compositions and methods for the treatment of drug-induced long QT syndrome and other cardiac channelopathies are disclosed herein. The compositions and methods of the present invention comprise binding one or more QT prolonging drugs with a liposome prior to parenteral (intravenous or subcutaneous) administration, or administration of an empty liposome prior to or concomitantly with therapeutic agents known to have a high risk of QT prolongation, or immediately following an envenomation. The results presented show an abrogation of the adverse effects of QT prolonging drugs in a dose-dependent manner by the compositions of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation patent application of U.S. patentapplication Ser. No. 14/268,376 filed May 2, 2014, which is acontinuation patent application of U.S. patent application Ser. No.13/487,233 filed Jun. 3, 2012, now U.S. Pat. No. 8,753,674 issued onJun. 17, 2014, which is a non-provisional application of U.S.Provisional Application Ser. No. 61/493,257 filed Jun. 3, 2011, theentire contents of which are incorporated herein by reference.

STATEMENT OF FEDERALLY FUNDED RESEARCH

None.

REFERENCE TO A SEQUENCE LISTING

None.

TECHNICAL FIELD OF THE INVENTION

The present invention relates in general to pharmacology and cardiology,and more particularly to liposomal based compositions and methods totherapeutically alter a genetic, drug-induced, or envenomous abnormallyprolonged QT interval.

BACKGROUND OF THE INVENTION

Without limiting the scope of the invention, its background is describedin connection with compositions and methods for controlling the durationof repolarization of the cardiac ventricle QT in a subject comprisingadministering to subject in need thereof of a modification of orfunctional interference with a therapeutic agent, or congenital defectwhich if unmodified can induce prolongation of repolarization in theheart myocyte action potential, torsade de points, and the long QTsyndrome. The present invention comprises of either binding a QTprolonging drug with a liposome prior to parenteral (intravenous orsubcutaneous) administration, or administration of an empty liposomeprior to or concomitantly with therapeutic agents known to have a highrisk of QT prolongation, or immediately following an envenomation.

The beating of the heart is due to precisely controlled regularly spacedwaves of myocardial excitation and contraction. The electrical currentsduring ion-based depolarization and repolarization can be measured byelectrical leads placed on the body in specific locations (theelectrocardiogram) which measure electrical waves. The P-wave representsa wave of depolarization in the atrium. When the entire atria becomesdepolarized, the wave returns to zero. After 0.1 seconds the ventricleis entirely depolarized resulting in the QRS complex. The three peaksare due to the way the current spreads in the ventricles. This isfollowed by the T-wave or repolarization of the ventricle. The QTinterval measured from the beginning of the QRS complex to the end ofthe T wave on the standard ECG represents the duration till thecompletion of the repolarization, phase of the cardiac myocyte (or thedepolarization and repolarization of the ventricle). The duration ofthis interval can vary due to genetic variation, cardiac disease,electrolyte balance, envenomation, and drugs. Prolongation of the QTinterval, can result in ventricular arrhythmias, and sudden death.

Drug induced long QTc Syndrome (LQTS) i.e., a prolongation of the actionpotential duration is a common cause of governmental mandated drugwithdrawal. QTc prolongation is an unpredictable risk factor forTorsades de Pointes (TdP), a polymorphic ventricular tachycardia leadingto ventricular fibrillation. Drug induced LQTS comprises about 3% of allprescriptions which when followed by TdP may constitute a lethal adversereaction. Patients taking one or more than one QTc-prolonging drugconcomitantly, have an enhanced risk of TdP. While the overalloccurrence of TdP is statistically rare but clinically significant forthe affected individual, assay for this drug effect is a mandatoryrequirement prior to allowing a drug to enter clinical trials.

Common structurally diverse drugs block the human ether-a-g-go-relatedgene (KCNH2 or hERG) coded K⁺ channel and the cardiac delayed-rectifierpotassium current I_(K) (KV11.1) resulting in acquired LQTS.Drug-associated increased risk of LQTS is a major drug developmenthurdle and many drugs have been withdrawn during pre-clinicaldevelopment, or assigned black box warnings following approval orwithdrawn from the market. Autosomal recessive or dominant LQTS basedupon 500 possible mutations in 10 different genes coding for thepotassium channel has an incidence of 1:3000 or about 100,000 persons inthe US. Prolonged QT intervals, or risk of LQTS occur in 2.5% of theasymptomatic US population. This syndrome when expressed can lead tosevere cardiac arrhythmia and sudden death in untreated patients. Theprobability of cardiac death in patients with asymptomatic congenitalLQTS who are medicated with LQTS-inducing drugs is increased.

The majority of the acquired LTQS drug withdrawals are due toobstruction of the potassium ion channels coded by the humanether-a-go-go related gene (hERG). High concentrations of hERG blockingdrugs generally induce a prolonged QTc interval and increase theprobability of TdP. Up to 10% of cases of drug-induced TdP can be due todue to 13 major genetic mutations, 471 different mutations, and 124polymorphisms (Chig, C 2006).

Systems and methods for detection of LQTS have been describedpreviously. For example U.S. Patent Publication No. 2010/0004549 (Kohlset al. 2010) discloses a system and method of detecting LQTS in apatient by comparing a collected set of ECG data from the patient to aplurality of databases of collected ECG data. The plurality of databaseswill include a database containing previous ECGs from the patient, aknown acquired LQTS characteristics database, and a known genetic LQTScharacteristics database. Comparing the patients ECG to these databaseswill facilitate the detection of such occurrences as changes in QTinterval from success of ECGs, changes in T-wave morphology, changes inU-wave morphology and can match known genetic patterns of LQTS. Thesystem and method is sensitive to patient gender and ethnicity, as thesefactors have been shown to effect LQTS, and is furthermore capable ofmatching a QT duration to a database of drug effects. The system andmethod is also easily integrated into current ECG management systems andstorage devices.

A system and method for the diagnosis and treatment of LQTS is describedin U.S. Patent Publication No. 20080255464 (Michael, 2008). The Michaelinvention includes a system for diagnosing Long QT Syndrome (LQTS)derives a QT/QS2 ratio from an electrical systole (QT) and a mechanicalsystole (QS2) to detect a prolonged QT interval in a patient's cardiaccycle. A processor acquires the systoles from a microphone and chestelectrodes, calculates the QT/QS2 ratio, and outputs the result to adisplay. The processor may compare the QT/QS2 ratio to a threshold valuestored in memory for diagnosing LQTS in the patient. A user interfaceprovides for programming, set-up, and customizing the display. A modeselector allows the system to operate alternatively as aphonocardiograph, a 12 lead electrocardiograph, or a machine fordiagnosing LQTS. A related method for diagnosing cardiac disorders suchas LQTS includes measuring QT and QS2 during a same cardiac cycle,calculating a QT/QS2 ratio, and comparing the result to a thresholdvalue derived from empirical data. The method may include measuringsystoles both at rest and during exercise, and may be used for drugefficacy, dosage optimization, and acquired LQTS causality tests.

A method for the treatment of cardiac arrhythmias is provided in U.S.Patent Publication No. 20070048284 (Donahue and Marban, 2007). Themethod includes administering an amount of at least one polynucleotidethat modulates an electrical property of the heart. The polynucleotidesof the invention may also be used with a microdelivery vehicle such ascationic liposomes and adenoviral vectors.

Methods, compositions, dosing regimes, and routes of administration forthe treatment or prevention of arrhythmias have been described by Fedidaet al. (2010) in U.S. Patent Publication No. 2001/00120890. In theFedida invention, early after depolarizations and prolongation of QTinterval may be reduced or eliminated by administering ion channelmodulating compounds to a subject in need thereof. The ion channelmodulating compounds may be cycloalkylamine ether compounds,particularly cyclohexylamine ether compounds. Also described arecompositions of ion channel modulating compounds and drugs which induceearly after depolarizations, prolongation of QT interval and/or Torsadesde Pointes. The Fedida invention also discloses antioxidants which maybe provided in combination with the ion channel modulating compounds,non-limiting examples of the antioxidants include vitamin C, vitamin E,beta-carotene, lutein, lycopene, vitamin B2, coenzyme Q10, cysteine aswell as herbs, such as bilberry, turmeric (curcumin), grape seed or pinebark extracts, and ginkgo.

SUMMARY OF THE INVENTION

The present invention describes compositions comprising a combination ofa liposome with a QTc- prolonging/TdP risk inducing drug, orenvenomation for treatment or reducing the the risk of syncope,seizure-like activity, and cardiac arrest. In one embodiment the instantinvention provides a composition for preventing one or more cardiacchannelopathies, conditions resulting from irregularities or alterationsin cardiac patterns, or both in a human or animal subject comprising:(i) one or more pharmacologically active agents selected from one ormore drug classes comprising β-blockers, sodium channel blockers,potassium supplements, potassium channel openers, hERG currentenhancers, calcium channel blockers, agents for correcting traffickingdefects, gap junction coupling enhancers, or any combinations thereof;(ii) one or more liposomes, wherein the liposomes are empty liposomesand administered prior to, concomitantly, or after administration of thepharmacologically active agent; and (iii) an optional pharmaceuticallyacceptable dispersion medium, solvent, or vehicle, wherein the activeagent, the liposome or both are dissolved, dispersed, or suspended inthe medium, the solvent, or the vehicle. The composition as disclosedherein may further comprise one or more optional pharmaceuticallyacceptable excipients selected from the group consisting of diluents,preservatives, lubricants, emulsifiers, coloring agents, thickeningagents, flavoring agents, fillers, bulking agents, or any combinationsthereof.

In one aspect of the instant invention the cardiac channelopathy or thecondition resulting from the irregularity or alteration in the cardiacpattern is selected from the group consisting of long QT syndrome(LQTS), atrial flutter, atrial fibrillation, ventricular tachycardia,sinus bradycardia, sinus tachycardia, atrial tachycardia, atrialfibrillation, atrial flutter, atrioventricular nodal block,atrioventricular node reentry tachycardia, atrioventricularreciprocating tachycardia, ventricular tachycardia, ventricularfibrillation, or any combinations thereof. In a specific aspect thecardiac condition is LQTS. In a related aspect LQTS is a drug-inducedcondition, a genetic condition, or both. In another aspect thecomposition is used for the treatment or prevention of LQTS induced byadministration of one or more drugs used in the treatment of cardiac ornon-cardiac related diseases, wherein the one or more drugs compriseAloxi or palonasitron HCL, Amiodarone, Arsenic trioxide, Astemizole,Bepridil, Chloroquine-Chlorpheniramine, Chlorpromazine, Cisapride,Celaxa, Clarithromycin, Erythromycin, Curcumin, Disopyramide,Dofetilide, Domperidone, Doxorubicin, Dronedarone, Droperidol,Grepafloxacin, Haldol, Haloperidol, Halofantrine, Ibutilide,Levomethadyl, Lidoflazine, Loratidine, Lovostatin, Mesoridazone,Methadone, Methanesulphonanilide (E-4031), Moxifloxacin, Pentamadine,Pimozide, Prenylamine, Probucol, Procainamide, Propafenone, Pyrilamine,Quinidine-Terfenidine, Sertindole, Sotalol, Sparfloxacin, andThioridazine.

In yet another aspect the composition is adapted for parenteral or oraladministration and the active agent, the liposome, or both are adaptedfor oral or parenteral administration. In another aspect the activeagent and the liposomes may be bound or conjugated together or isencapsulated or enclosed in the one or more liposomes. In another aspectthe active agent and the liposome may be mixed together by shaking forconcomitant administration to the human or animal subject. The liposomesdescribed hereinabove may comprise spherical anionic, cationic, orneutral liposomes with a diameter ranging from 10 nm-200 nm and furthercomprises a lipid or a phospholipid wall, wherein the lipids or thephospholipids are selected from the group consisting ofphosphatidylcholine (lecithin), lysolecithin,lysophosphatidylethanol-amine, phosphatidylserine, phosphatidylinositol,sphingomyelin, phosphatidylethanolamine (cephalin), cardiolipin,phosphatidic acid, cerebrosides, dicetylphosphate, phosphatidylcholine,and dipalmitoyl-phosphatidylglycerol, stearylamine, dodecylamine,hexadecyl-amine, acetyl palmitate, glycerol ricinoleate, hexadecylsterate, isopropyl myristate, amphoteric acrylic polymers, fatty acid,fatty acid amides, cholesterol, cholesterol ester, diacylglycerol, anddiacylglycerol succinate.

Another embodiment of the instant invention discloses a composition forpreventing or treating one or more adverse reactions arising fromadministration of a therapeutically active agent or a drug in a human oranimal subject comprising: one or more liposomes, wherein the liposomesare empty liposomes and administered prior to, concomitantly, or afteradministration of the therapeutically active agent or the drug and anoptional pharmaceutically acceptable dispersion medium, solvent, orvehicle, wherein the active agent, the liposome or both are dissolved,dispersed, or suspended in the medium, the solvent, or the vehicle. Inone aspect the therapeutically active agent or a drug is used in aprevention or a treatment of one or more cardiac or non-cardiac diseasesin the human or animal subject. In another aspect the one or moreadverse reactions comprise one or more cardiac channelopathies,irregularities or alterations in cardiac patterns, or both. In aspecific aspect the adverse reaction is LQTS. In yet another aspect thecomposition is adapted for parenteral or oral administration, and thetherapeutically active agent active agent or the drug may be bound,conjugated, encapsulated, or enclosed in the one or more liposomes. In arelated aspect the therapeutically active agent active agent or the drugand the liposome may be mixed together by shaking for concomitantadministration to the human or animal subject.

In yet another embodiment the instant invention relates to a method forpreventing or treating one or more cardiac channelopathies,irregularities or alterations in cardiac patterns, or both in a human oranimal subject comprising: i) identifying the human or animal subject inneed of prevention or treatment of the one or more cardiacchannelopathies, irregularities or alterations in cardiac patterns, orboth and administering to the human or animal subject a therapeuticallyeffective amount of a composition comprising: (a) one or morepharmacologically active agents selected from one or more drug classescomprising β-blockers, sodium channel blockers, potassium supplements,potassium channel openers, hERG current enhancers, calcium channelblockers, agents for correcting trafficking defects, gap junctioncoupling enhancers, or any combinations thereof, (b) one or moreliposomes, wherein the liposomes are empty liposomes and administeredprior to, concomitantly, or after administration of thepharmacologically active agent, and (c) an optional pharmaceuticallyacceptable dispersion medium, solvent, or vehicle, wherein the activeagent, the liposome or both are dissolved, dispersed, or suspended inthe medium, the solvent, or the vehicle. In one aspect the cardiacchannelopathy or the condition resulting from the irregularity oralteration in the cardiac pattern is selected from the group consistingof long QT syndrome (LQTS), atrial flutter, atrial fibrillation,ventricular tachycardia, sinus bradycardia, sinus tachycardia, atrialtachycardia, atrial fibrillation, atrial flutter, atrioventricular nodalblock, atrioventricular node reentry tachycardia, atrioventricularreciprocating tachycardia, ventricular tachycardia, ventricularfibrillation, or any combinations thereof. In a specific aspect thecardiac condition is LQTS which may be a drug-induced condition, agenetic condition, or both.

In another aspect the composition is used for the treatment orprevention of LQTS induced by administration of one or more drugs usedin the treatment of cardiac or non-cardiac related diseases, wherein theone or more drugs comprise Aloxi or palonasitron HCL, Amiodarone,Arsenic trioxide, Astemizole, Bepridil, Chloroquine-Chlorpheniramine,Chlorpromazine, Cisapride, Celaxa, Clarithromycin, Erythromycin,Curcumin, Disopyramide, Dofetilide, Domperidone, Doxorubicin,Dronedarone, Droperidol, Grepafloxacin, Haldol, Haloperidol,Halofantrine, Ibutilide, Levomethadyl, Lidoflazine, Loratidine,Lovostatin, Mesoridazone, Methadone, Methanesulphonanilide (E-4031),Moxifloxacin, Pentamadine, Pimozide, Prenylamine, Probucol,Procainamide, Propafenone, Pyrilamine, Quinidine-Terfenidine,Sertindole, Sotalol, Sparfloxacin, and Thioridazine. In another aspectthe composition is administered to the human or animal subjectparenterally or orally. In yet another aspect the therapeutically activeagent active agent or the drug may be bound, conjugated, encapsulated,or enclosed in the one or more liposomes or may be mixed together byshaking for concomitant administration to the human or animal subject.In another aspect the liposomes comprise one or more spherical anionic,cationic, or neutral liposomes having an average diameter ranging from10 nm-200 nm.

In one embodiment the instant invention provides a method for preventingor treating one or more adverse reactions arising from administration ofa therapeutically active agent or a drug in a human or animal subjectcomprising: identifying the human or animal subject in need ofprevention or treatment of the one or more adverse reactions arisingfrom the administration of the therapeutically active agent or the drug,and administering to the human or animal subject a therapeuticallyeffective amount of a composition. The composition used in the method ofthe present invention comprises: one or more liposomes, wherein theliposomes are empty liposomes and administered prior to, concomitantly,or after administration of the therapeutically active agent or the drugand an optional pharmaceutically acceptable dispersion medium, solvent,or vehicle, wherein the active agent, the liposome or both aredissolved, dispersed, or suspended in the medium, the solvent, or thevehicle.

In one aspect the therapeutically active agent or a drug is used in aprevention or a treatment of one or more cardiac or non-cardiac diseasesin the human or animal subject. In another aspect the one or moreadverse reactions comprise one or more cardiac channelopathies,irregularities or alterations in cardiac patterns, or both. In yetanother aspect the cardiac channelopathy or the irregularity oralteration in the cardiac pattern, or both are selected from the groupconsisting of long QT syndrome (LQTS), atrial flutter, atrialfibrillation, ventricular tachycardia, sinus bradycardia, sinustachycardia, atrial tachycardia, atrial fibrillation, atrial flutter,atrioventricular nodal block, atrioventricular node reentry tachycardia,atrioventricular reciprocating tachycardia, ventricular tachycardia,ventricular fibrillation, or any combinations thereof.

In related aspects of the method the therapeutically active agent or adrug is selected from one or more drug classes comprising 13-blockers,sodium channel blockers, potassium supplements, potassium channelopeners, hERG current enhancers, calcium channel blockers, agents forcorrecting trafficking defects, gap junction coupling enhancers, or anycombinations thereof and the therapeutically active agent or the drugcomprises Aloxi or palonasitron HCL, Amiodarone, Arsenic trioxide,Astemizole, Bepridil, Chloroquine-Chlorpheniramine, Chlorpromazine,Cisapride, Celaxa, Clarithromycin, Erythromycin, Curcumin, Disopyramide,Dofetilide, Domperidone, Doxorubicin, Dronedarone, Droperidol,Grepafloxacin, Haldol, Haloperidol, Halofantrine, Ibutilide,Levomethadyl, Lidoflazine, Loratidine, Lovostatin, Mesoridazone,Methadone, Methanesulphonanilide (E-4031), Moxifloxacin, Pentamadine,Pimozide, Prenylamine, Probucol, Procainamide, Propafenone, Pyrilamine,Quinidine- Terfenidine, Sertindole, Sotalol, Sparfloxacin, andThioridazine. In one specific aspect the adverse reaction is LQTS. Inone aspect the composition comprises one or more optionalpharmaceutically acceptable excipients selected from the groupconsisting of diluents, preservatives, lubricants, emulsifiers, coloringagents, thickening agents, flavoring agents, fillers, bulking agents, orany combinations thereof and is administered to the human or animalsubject parenterally or orally. In another aspect the therapeuticallyactive agent active agent or the drug may be bound, conjugated,encapsulated, or enclosed in the one or more liposomes. In yet anotheraspect the therapeutically active agent active agent or the drug and theliposome may be mixed together by shaking for concomitant administrationto the human or animal subject.

Another embodiment of the present invention relates to a composition forpreventing or treating long QT syndrome (LQTS) arising fromadministration of Terfenidine, Methanesulphonanilide (E-4031), or anyother active agent for treatment of a cardiac condition or a disease ina human or animal subject comprising: a) one or more liposomes, whereinthe liposomes are empty liposomes and administered prior to,concomitantly, or after administration of the Terfenidine,Methanesulphonanilide (E-4031), or any other active agent; and b) anoptional pharmaceutically acceptable dispersion medium, solvent, orvehicle, wherein the Terfenidine, Methanesulphonanilide (E-4031), or theany other active agent, the liposome or both are dissolved, dispersed,or suspended in the medium, the solvent, or the vehicle.

The present invention also further describes a method for preventing ortreating long QT syndrome (LQTS) arising from administration ofTerfenidine, Methanesulphonanilide (E-4031), or any other active agentfor treatment of a cardiac condition or a disease in a human or animalsubject comprising the steps of: (i) identifying the human or animalsubject in need of prevention or treatment of the LQTS arising from theadministration of Terfenidine, Methanesulphonanilide (E-4031), or anyother active agent; and (ii) administering to the human or animalsubject a therapeutically effective amount of a composition comprising:one or more liposomes, wherein the liposomes are empty liposomes andadministered prior to, concomitantly, or after administration of theTerfenidine, Methanesulphonanilide (E-4031), or any other active agent;and an optional pharmaceutically acceptable dispersion medium, solvent,or vehicle, wherein the Terfenidine, Methanesulphonanilide (E-4031), orthe any other active agent, the liposome or both are dissolved,dispersed, or suspended in the medium, the solvent, or the vehicle.

In yet another embodiment the instant invention provides a compositionfor treating or preventing long QT syndrome (LQTS) arising fromadministration of a therapeutically effective amount of curcumin for atreatment of one or more diseases or conditions comprising: one or moreliposomes, wherein the liposomes are empty liposomes and administeredprior to, concomitantly, or after administration of the therapeuticallyeffective dosage amount of curcumin and an optional pharmaceuticallyacceptable dispersion medium, solvent, or vehicle, wherein the one ormore liposomes are dissolved, dispersed, or suspended in the medium, thesolvent, or the vehicle. In one aspect the one or more diseases treatedby the therapeutically effective amount of the curcumin comprises type 2diabetes and one or more associated pathological conditions (sequelae),proliferative disorders selected from the group consisting of breast,uterine, cervical, ophthalmic, pancreatic cancer, or any combinationsthereof, or more neurological or neurodegenerative conditions selectedfrom the group consisting of Parkinson's disease (PD), Alzheimer'sdisease, stress disorders, senile dementia, vascular dementias, Pick'sdisease, Creutzfeldt-Jacobs disease, post-traumatic stress disorder(PTSD) and aging. In another aspect the therapeutically effective amountof curcumin comprises curcumin, curcumin analogues, curcuminderivatives, slow or sustained release formulations comprising curcuminenclosed in a biodegradable polymeric nanoparticle, wherein thebiodegradable polymer comprises poly-lactic glycolic acid (PLGA)copolymer.

The present invention further provides a method for treating orpreventing long QT syndrome (LQTS) in a human subject taking atherapeutically effective amount of curcumin for a treatment of one ormore diseases or conditions comprising the steps of: identifying thehuman subject taking a therapeutically effective amount of curcumin forthe treatment of one or more diseases or conditions; and administeringto the human subject a composition comprising: (i) one or moreliposomes, wherein the liposomes are empty liposomes and administeredprior to, concomitantly, or after administration of the therapeuticallyeffective amount of curcumin and (ii) an optional pharmaceuticallyacceptable dispersion medium, solvent, or vehicle, wherein the one ormore liposomes are dissolved, dispersed, or suspended in the medium, thesolvent, or the vehicle.

One embodiment of the instant invention describes a pharmaceuticalcomposition of curcumin for treatment or prevention of one or moredisorders comprising: one or more spherical liposomes or nanoparticlescomprising curcumin, curcumin analogues, synthetic curcumin, curcuminderivatives, slow or sustained release formulations enclosed orencapsulated in a lipid or a phospholipid wall and an optionalpharmaceutically acceptable dispersion medium, solvent, or vehicle,wherein the one or more liposomes are dissolved, dispersed, or suspendedin the medium, the solvent, or the vehicle. In one aspect thecomposition prevents or corrects one or more adverse reactions inducedby curcumin. In another aspect the one or more adverse reactions areselected from the group consisting of long QT syndrome (LQTS), atrialflutter, atrial fibrillation, ventricular tachycardia, sinusbradycardia, sinus tachycardia, atrial tachycardia, atrial fibrillation,atrial flutter, atrioventricular nodal block, atrioventricular nodereentry tachycardia, atrioventricular reciprocating tachycardia,ventricular tachycardia, ventricular fibrillation, or any combinationsthereof. In a specific aspect the adverse reaction is LQTS.

Finally, a method for treating a human subject suffering from one ormore diseases or disorders with a therapeutically effective amount of acurcumin composition is also disclosed herein. The method comprises thesteps of: a) identifying the human subject suffering from one or moredisorders treatable by the therapeutically effective amount of thecurcumin and administering to the human subject a pharmaceuticalcomposition comprising the therapeutically effective amount of thecurcumin, wherein the composition comprises: one or more sphericalliposomes or nanoparticles comprising curcumin, curcumin analogues,synthetic curcumin, curcumin derivatives, slow or sustained releaseformulations enclosed or encapsulated in a lipid or a phospholipid walland an optional pharmaceutically acceptable dispersion medium, solvent,or vehicle, wherein the one or more liposomes are dissolved, dispersed,or suspended in the medium, the solvent, or the vehicle.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the features and advantages of thepresent invention, reference is now made to the detailed description ofthe invention along with the accompanying figures and in which:

FIG. 1 is a plot showing the effect of terfenadine on hERG currentdensity from transfected HEK 293 cells at 20 mV;

FIG. 2 is a plot of the current-voltage (I-V) relationship of hERGcurrent amplitude from transfected HEK 293 cells exposed to terfenadine;

FIG. 3 is a plot of the effect of terfenadine on hERG current densityfrom transfected HEK 293 cells at 20 mV;

FIG. 4 is a plot of the I-V relationship of hERG current amplitude fromtransfected HEK 293 cells exposed to terfenadine;

FIG. 5 is a plot showing the effect of E-4031 on hERG current densityfrom transfected HEK 293 cells at 20 mV;

FIG. 6 is a plot of the effect of curcumin on hERG current density fromtransfected HEK 293 cells at 20 mV;

FIG. 7 is a plot of the I-V relationship of hERG current amplitude fromtransfected HEK 293 cells exposed to curcumin;

FIG. 8 is a plot showing the effect of curcumin (as liposomal curcumin)on hERG current density from transfected HEK 293 cells at 20 mV;

FIG. 9 is a plot showing the I-V relationship of hERG current amplitudefrom transfected HEK 293 cells exposed to Curcumin (as liposomalcurcumin);

FIG. 10 is a plot showing the effect of Curcumin (Liposomes+Curcumin) onhERG current density from transfected HEK 293 cells at 20 mV;

FIG. 11 is a plot of the I-V relationship of hERG current amplitude fromtransfected HEK 293 cells exposed to Curcumin (Liposomes+Curcumin);

FIG. 12 shows the effect of liposomes on hERG current density fromtransfected HEK 293 cells at 20 mV;

FIG. 13 is a plot of the I-V relationship of hERG current amplitude fromtransfected HEK 293 cells exposed to liposomes;

FIG. 14 is a plot showing the of liposomes+E-4031 on hERG currentdensity from transfected HEK 293 cells at 20 mV;

FIG. 15 is a plot of the I-V relationship of hERG current amplitude fromtransfected HEK 293 cells exposed to Liposomes+E-4031;

FIG. 16 is a plot showing the effect of liposomes+terfenadine on hERGcurrent density from transfected HEK 293 cells at 20 mV; and

FIG. 17 is a plot showing the I-V relationship of hERG current amplitudefrom transfected HEK 293 cells exposed to liposomes+terfenadine.

DETAILED DESCRIPTION OF THE INVENTION

While the making and using of various embodiments of the presentinvention are discussed in detail below, it should be appreciated thatthe present invention provides many applicable inventive concepts thatcan be embodied in a wide variety of specific contexts. The specificembodiments discussed herein are merely illustrative of specific ways tomake and use the invention and do not delimit the scope of theinvention.

To facilitate the understanding of this invention, a number of terms aredefined below. Terms defined herein have meanings as commonly understoodby a person of ordinary skill in the areas relevant to the presentinvention. Terms such as “a”, “an” and “the” are not intended to referto only a singular entity, but include the general class of which aspecific example may be used for illustration. The terminology herein isused to describe specific embodiments of the invention, but their usagedoes not delimit the invention, except as outlined in the claims.

As used herein the term “Curcumin (diferuloyl methane;1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione)” is anaturally occurring compound which is the main coloring principle foundin the rhizomes of the plant Curcuma longa (U.S. Pat. No. 5,679,864,Krackov et al.).

The term “liposome” refers to a capsule wherein the wall or membranethereof is formed of lipids, especially phospholipid, with the optionaladdition therewith of a sterol, especially cholesterol.

As used herein, the term “in vivo” refers to being inside the body. Theterm “in vitro” used as used in the present application is to beunderstood as indicating an operation carried out in a non-livingsystem.

As used herein, the term “receptor” includes, for example, moleculesthat reside on the surface of cells and mediate activation of the cellsby activating ligands, but also is used generically to mean any moleculethat binds specifically to a counterpart. One member of a specificbinding pair would arbitrarily be called a “receptor” and the other a“ligand.” No particular physiological function need be associated withthis specific binding. Thus, for example, a “receptor” might includeantibodies, immunologically reactive portions of antibodies, moleculesthat are designed to complement other molecules, and so forth. Indeed,in the context of the present invention, the distinction between“receptor” and “ligand” is entirely irrelevant; the invention concernspairs of molecules, which specifically bind each other with greateraffinity than either binds other molecules. However, for ease ofexplanation, the invention method will be discussed in terms of targetreceptor (again, simply a molecule for which a counterpart is soughtthat will react or bind with it) and “ligand” simply represents thatcounterpart.

As used herein, the term “treatment” refers to the treatment of theconditions mentioned herein, particularly in a patient who demonstratessymptoms of the disease or disorder.

As used herein, the term “treatment” or “treating” refers to anyadministration of a compound of the present invention and includes (i)inhibiting the disease in an animal that is experiencing or displayingthe pathology or symptomatology of the diseased (i.e., arresting furtherdevelopment of the pathology and/or symptomatology); or (ii)ameliorating the disease in an animal that is experiencing or displayingthe pathology or symptomatology of the diseased (i.e., reversing thepathology and/or symptomatology). The term “controlling” includespreventing treating, eradicating, ameliorating or otherwise reducing theseverity of the condition being controlled.

The terms “effective amount” or “therapeutically effective amount”described herein means the amount of the subject compound that willelicit the biological or medical response of a tissue, system, animal orhuman that is being sought by the researcher, veterinarian, medicaldoctor or other clinician.

The terms “administration of” or “administering a” compound as usedherein should be understood to mean providing a compound of theinvention to the individual in need of treatment in a form that can beintroduced into that individual's body in a therapeutically useful formand therapeutically useful amount, including, but not limited to: oraldosage forms, such as tablets, capsules, syrups, suspensions, and thelike; injectable dosage forms, such as IV, IM, or IP, and the like;transdermal dosage forms, including creams, jellies, powders, orpatches; buccal dosage forms; inhalation powders, sprays, suspensions,and the like; and rectal suppositories.

As used herein the term “intravenous administration” includes injectionand other modes of intravenous administration.

The term “pharmaceutically acceptable” as used herein to describe acarrier, diluent or excipient must be compatible with the otheringredients of the formulation and not deleterious to the recipientthereof.

Compositions and methods for controlling the duration of repolarizationof the cardiac ventricle QT interval are disclosed herein. The method ofthe present invention comprises comprising administering to subject inneed thereof of a modification of or a functional interference with atherapeutic agent, or a congenital defect which if unmodified can induceprolongation of repolarization in the heart myocyte action potential,torsade de points, and the long QT syndrome. The present inventioncomprises of either binding a QT prolonging drug with a liposome priorto parenteral (intravenous or subcutaneous) administration, or emptyliposomal administration prior to or concomitantly with one or moretherapeutic agents known to have a high risk of QT prolongation, orimmediately following an envenomation. The findings of the presentinvention indicate that the adverse effect of curcumin and other QTprolonging drugs is abrogated with liposomal curcumin, and with vortexedmixtures of empty liposomes in a dose dependent manner.

Ion channels are pore-forming integral membrane proteins that establishand control the electrochemical gradient (the action potential) acrossthe plasma membrane, and intracellular organelles of cells by modulatingion. The channels are assembled as a circular arrangement of proteinspacked around a water-filled pore. The ions passage through the channelin single file, which may be open or closed by chemical, electricalsignals, temperature, or mechanical force. Ion channel dysfunction maybe associated with mutations in the genes coding these channels or withdrugs interfering with ion flow. Dysfunction in cardiac electrolytepotassium, calcium, and sodium channels in the cardiac myocyte membraneinduces defects in electrical currents, and the normal action potentialwhich are necessary for coordinated myocyte contraction and maintenanceof normal blood circulation resulting in clinical cardiac symptoms. Thecentral roles of the 40 members, and 12 subfamilies of voltage gatedpotassium channel's (Kv) role are to repolarize the cell membranefollowing action potentials. The flux of potassium ions in the cardiacmyocyte K⁺ channels modulates electrolytic currents, levels ofdepolarization and repolarization. Congenital and/or drug-inducedchannel defects are associated with morbidity and mortality in otherwiseasymptomatic individuals. The channel proper coded by the gene KCNH2 orhERG (human ether-a-go-go-related gene) contains proteins designated asKv11.1 and the Lv11.1 α-subunit of the rapidly activating rectifier K⁺current I_(Kr). This cell membrane channel mediates the “rapid” delayedrectifier current I_(Kr), by conducting K⁻ ions out of the cardiacmyocytes and is a critical mechanism to allow the cardiac potential toreturn to the resting state (repolarization).

Even though the hERG channel pore-domain lacks a known three-dimensionalstructure, insight into its putative structure has been gained fromsite-directed mutagenesis data (Stansfeld P J, 2007). Within the hERGchannel pore cavity, ion flux and currents can be modified dependingupon the open or closed states, and by drug interactions at key highaffinity drug binding sites. These sites are the aromatic amino-acidresidues (Y652 and F656) on the inner helices of the pore. The mostimportant currents mediated by drugs, the sensitive delayed, I_(Kr),(rapid) current which repolarizes the myocardial cells and the I_(Ks),(slow) rectifier currents are exhibited on the standardelectrocardiogram (ECG) as the QT interval which when corrected forheart rate this is conventionally defined as QTc.

Congenital defects in ion channels first described by Jervell A, (1957),alter the balance of currents determining repolarization of the actionpotential and predispose to LQTS arrhythmias.and sudden cardiac death.Mutations have been identified giving rise to subtypes of congenitalLQTS, familial arrhythmogenic syndromes characterized by abnormal ionchannel function, delayed repolarization, prolonged QT interval on theelectrocardiogram and a life-threatening polymorphic ventriculartachycardia known as torsade de points. Different mutations in the hERGgene and its coded proteins translate to defects in channel function anda number of clinical syndromes. Type 2 congenital long-QT syndrome(LQT2) results from A614V missense mutations in the KCNH gene and ischaracterized by four classes of loss of Kv11.1 protein and consequentchannel dysfunction. These abnormal Kv11.1 channels include (class 1), adominant-intracellular trafficking-deficient ion channel protein:usually due to missense mutations, (Class 2), a correctible phenotypewhen cells are incubated for 24 hours at 27° temperature, or withexposure to the drugs E-4031 (Zhou Z 1999 (class 3)), channel gating,and (class 4) permeation)(Anderson C. L., 2006). Blockade by any ofthese and particularly the “rapid” current prolongs the action potentialand manifests on the ECG as a prolonged QT interval and emergence ofother T or U wave abnormalities. Under such circumstances, activation ofan inward depolarization current induces increased dispersion ofrepolarization. The latter results in a heterogeneous recovery ofexcitability, and induction of torsades de points (TdP) an earlypremature ventricular contraction (PVC). (R-0n-T). This is whereventricular depolarization i.e, the R-wave occurs simultaneously withthe relative refractory period at the end of repolarization (latter halfof the T-wave) and initiates pathologic T-U waves and torsades.Sustained TdP leads to a zone of functional refractoriness in themyocardium, and cardiac arryhthmias. The ECG reading in torsadesexhibits a rapid polymorphic ventricular tachycardia with acharacteristic twist of the QRS complex around the isoelectric baseline.This is characterized by a rotation of the heart's electrical axis by asmuch as 180°, long and short RR- intervals, and clinically this leads toa fall in arterial blood pressure, syncope, degeneration intoventricular fibrillation and sudden death.

On the ECG, retardation of the I_(Kr), current interval is synonymouswith QT prolongation when greater than 440 ms in men and 460 ms inwomen. Pharmacological inhibition of hERG K⁺ channels by structurallyand therapeutically diverse drugs translates to the clinical acquiredform of the long QT syndrome (LQTS). While QT prolonging drugs representtwo to three percent of the total prescriptions in the developed worldthe reported incidence of QT prolongation and dosage variessignificantly within different drug classes. The latter include Class 1Aand class III antiarrhythmics, antihistamines, antimicrobials,antipsychotics, tricyclic antidepressants, prokinetics, andanti-anginals. Recently, curcuminoids were reported to block humancardiac K⁺ channels. (Moha ou Maati H, 2008).

Increased incidence of QT prolongation may also occur in the presence ofhypomagnesemia. hypokalemia, hypocalcalcemia, hypoxia, acidosis, heartfailure, left ventricular hypertrophy, slow heart rate, female gender,hypothermia, and subarachnoid hemorrhage. The severity of arrhythmia ata given QT interval, and development of TdP varies from drug to drug andpatient to patient and may not be linearly related to the dose or plasmaconcentration of a specific drug. However, antiarrhythmic cardiac drugsaffecting the potassium (K⁺) efflux (Class III) and non-cardiac drugs:that significantly alter repolarization, as measured by prolongation ofthe QT interval predispose the patient to torsades. Additional factorsassociated with an increased tendency toward TdP include familial longQT syndrome (LQTS). The most common causes of familial LQTS aremutations in genes.

KCNQ1 codes for KvLTQ1, the alpha subunit of the slow delayed potassiumrectifier potassium channel is highly expressed in the heart. Thecurrent through the heteromeric channel when interacting with the minKbeta subunit is known as I_(Ks). When missense mutated it reduces theamount of repolarizing current needed to terminate the action potential.These LTQ1 mutations represent 35% of all cases, and are the leastsevere, usually causing syncope.

KCNH2 or the hERG gene when mutated represents 30% of all genetic cases,and is the subunit of the rapid delayed rectifier potassium channelhERG+MiRP1. Current through this channel known as I_(Kr), is responsiblefor termination of the action potential and the length of the QTinterval. When reduced it leads to LQT2. The rapid current is not onlythe most drug sensitive, but also is associated with the pro-arrhythmiceffect in His-Purkinje cells and M cells in the mid-ventricularmyocardium. Drug induced LQTs occurs with anti-arrhythmic drugs,antihistamines, anti-psychotic and other drugs. The combination ofgenetic LQTS and LQTS-inducing drugs increase succeptibility to lethalside effects. Most drugs causing LKTS block the I_(Kr) current via thehERG gene. This channel exhibits unintended drug binding at tyrosine 652and phenylalanine 656 which when bound block current conduction.Uncommon but lethal mutations in gene SCN5A slow inactivation of thealpha subunit of the sodium channel, prolonging Na⁺ influx and thecurrent I_(Na) during depolarization. Continued depolarizing currentthrough the channel late in the action potential induces a late burstingcurrent (LQT3).

L-type calcium channels re-open during the plateau phase of the actionpotential following LQTS as “early after depolarizations.” Theiractivity is sensitive to adrenergic stimulation and increases the riskof sudden death during adrenergic states in the presence of impairedrepolarization. In these subjects TdP can be precipitated followingexercise, or emotional surprise unrelated to drugs. There are additionaluncommon and rare mutations designated LQT4-13.

Apart from heart rate, the QT duration varies with recording andmeasurement techniques, sympatho-vagal activity, drugs, electrolytedisorders, cardiac or metabolic diseases, diurnal variation and geneticLQT2 mutations. These parameters cause the reported incidence ofdrug-induced TdP to be loosely associated with clinical studies duringdrug development, post-marketing surveillance, epidemiologic studies,and anecdotal case reports. Detection of QT prolongation duringpre-clinical drug development can lead to abandonment and precludes anyall-inclusive accounting of the actual incidence of drug related QTprolongation (Yap 2003). A number of QT-prolonging drugs have beenwithdrawn either during development or after being on the market. Theseinclude Terfenadine, Astemizole, Gripafloxacin, Terodilene, Droperidole,Lidoflazine, Levomethadyl, Sertindoyle, levomethadyl, and Cisapride.

Genetic and age related susceptibility: there are pre-dispositions toQT-prolonging drug events: this includes patients with structural heartdisease, taking hepatic C450 inhibitors, who have a geneticpredisposition, or DNA polymorphisms. Old females generally are moresusceptible than young females, while young males have increasedsusceptibility compared to elderly males.

Current Therapy for QT prolonging-drugs, and in genotypic QTsensitivity: Pharmacological therapy: first line treatment for LQTS, apotentially lethal disease with a 13% incidence of cardiac arrest andsudden death. (i) Dexrazoxane: (a piperazinedione cyclic derivative ofedetic acid). It diminishes but does not eliminate the potential foranthracycline induced cardiotoxicity associated with over 300 mg/M²epirubicin administered to patients with breast cancer. Use ofintravenous Dexrazoxane is limited to anthracyclines only, i.e. it iscontraindicated in chemotherapy regimens that do not contain ananthracycline. (ii) β-blockers: propranolol as sympathetic stimulationtherapy may decrease risk of cardiac events by 81% in LQT1, it may alsosuppress isoproteranolol augmentation of transmural dispersion ofrepolarization (TDR) and TdP, however on adequate propranolol treatment10% still develop cardiac events. In LQT2 subjects, cardiac event riskis decreased 59%, however 23% still develop cardiac events. (iii) Sodiumchannel blockers: 32% of LQT3 subjects develop cardiac events onadequate propranolol. In these subjects with low heart rates, β-blockersmay increase dispersion of repolarization and risk of TdP. LQT3 subjectswith sodium channel mutations preventing inactivation and inducingpersistant increase in late I_(Na) during phase 2 of the actionpotential, a cause of QT prolongation using, mexiletine (Shimizu W,1997) a class D3 sodium channel blocker abbreviates the QT interval byreduction of TDR. (iv) Potassium supplementation: both I_(Kr), andI_(K1) are sensitive to extracellular potassium levels. Raising plasmaconcentration by 1.5 mEq/L above baseline can reduce the QTc interval by24%(Compton 1996 and Etheredge 2003), but there is no evidence that ittranslates in arrhythmia protection. (v) Potassium channel openers:Nicorandil, a potassium channel opener given intravenously at 2-20umol/L appreviates the QT interval in LQT1 and LQT2 subjects.(Shimizu W2000). (vi) hERG current enhancers: RPR 260243 reversesdofetalide-induced action potential prolongation in guinea pig myocytes(Kang J 2005). (vii) Calcium channel blockers: Calcium influx throughL-type calcium channels maintains the plateau phase, the duration of theaction potential and the QT interval of the action potential. Verapamilan L-type calcium channel blocker, and inhibitor of I_(Na) abbreviatesthe QT interval and suppresses TdP in LQTS models is used in patientswith paroxysmal atria-ventricular nodal reentrant tachycardia withsignificantly shortened QT at low heart rates. The hERG inhibitory EC₅₀is 83 uM. When verapamil is administered at appropriate dosage, torsadesde points may be avoided (Fauchier L 1999). (viii) Trafficking defectscorrection: Defects in transport of proteins and glycoproteins formingtrans-membrane ion pores in the cardiac cell membrane reduce theamplitude of corresponding currents and have a role in LQTS.Fexofenadine, a metabolite of terfenadine or thapsigargin can rescuesuch defective trafficking without blocking hERG current in selectivemissense mutations associated with LQT2. (ix) Gap Junction couplingenhancers: Gap junctions are intercellular channels allowing both smallmolecules and current to be transferred between cardiac cells. Heartfailure and hypertrophy are associated with uncoupling of gap junctions.Enhancing gap junctions can produce an anti-arrhythmic effect wheredispersion of repolarization is enhanced in LQTS. Infusion of asynthetic peptide, AAP10 a gap junction enhancer reduces the QT intervalin the rabbit left ventricular preparation (Quan X Q, 2007).

This nonclinical laboratory study described in the present invention wasconducted in accordance with the United States Food and DrugAdministration (FDA) Good Laboratory Practice Regulations, 21 CFR Part58, the Organization for Economic Cooperation and Development (OECD)Principals of Good Laboratory Practice [C(97) 186/Final], issued Nov.26, 1997, and the Japanese Ministry of Health, Labour and Welfare (MHLW)Good Laboratory Practice Standards Ordinance No. 21, Mar. 26, 1997.

Study Outline: 1) Test articles: Curcumin, Empty Liposomes, Liposomalcurcumin, (0.014, 0.20, 3.4 and 11.4 μM); 2) Test System:hERG-expressing HEK 293 transfected cell line; 3) Test performed:Whole-cell patch-clamp current acquisition and analysis; 4) ExperimentalTemperature: 35±2° C.

Application of test article: 1) 5 minutes of exposure to eachconcentration in presence of closed circuit perfusion (2 mL/min); 2) 5minutes for washout periods in presence of a flow-through perfusion (2mL/min) in addition to a closed circuit perfusion (2 mL/min); 3) Thepositive controls, (100 nM E-4031, and Terfenadine (0.01, 0.03, 0.1 uM)were added to naive cells obtained from the same cell line and samepassage for a period of 5 minutes in presence of a closed circuitperfusion (2 mL/min); 4) Curcumin, Terfenadine and E-4031 were eachvortexed for 15 minutes with empty liposomes, and then tested. Cellswere under continuous stimulation of the pulses protocol throughout thestudies and cell currents were recorded after 5 minutes of exposure toeach condition.

Data acquisition design: Acquisition Rate(s): 1.0 kHz. Design foracquisition when testing the compounds or the vehicle/solventequivalent: 1 recording made in baseline condition, 1 recording made inthe presence of concentration 1, 2, 3 or 4, and 1 recording made afterwashout (only after the fourth concentration). Design for acquisitionwhen testing the positive controls: 1 recording made in baselinecondition, 1 recording made in the presence of the positive control, andn=number of responsive cells patched on which the whole protocol abovecould be applied.

Statistical analysis: Statistical comparisons were made using pairedStudent's t-tests. For the test articles, the currents recorded afterexposure to the different test article concentrations were statisticallycompared to the currents recorded in baseline conditions. Currents,recorded after the washout, were statistically compared to the currentsmeasured after the highest concentration of test article. In the sameway, currents recorded after the positive control, were compared to thecurrents recorded in baseline conditions. Differences were consideredsignificant when p≦0.05.

Experimental Data Exclusion criteria: 1) Timeframe of drug exposure notrespected; 2) Instability of the seal; 3) No tail current generated bythe patched cell; 4) No significant effect of the positive control; and5) More than 10% variability in capacitance transient amplitude over theduration of the study.

The in vitro effects of curcumin, liposomal curcumin, empty liposome andpositive controls E-4031 and Terfenadine were determined on the humandelayed rectifier current using human embryonic kidney (HEK) 293 cellstransfected with the human ether-a-go-go-related gene (hERG).

There are a great number of drugs that are currently marketed withincreased risk of LQTS and TdP. Some non-limiting examples are presentedbelow:

Aloxi or palonasitron HCL: 5-hydroxytryptamine-3 receptor antagonist, anintravenous drug for post-operative nausea and vomiting.(Eisai Corp.Helsinn, Switz.) AE's include >2% EKG, 5% QT prolongation, 4%bradycardia, at doses above 2.25 mg.

Amiodarone (cordorone X) a class III antiarrhythmic agent, for WPWsyndrome, for ventricular arrhythmias: Females>males risk regarded aslow. 1-3% have predominantly class III effects. SA node dysfunction, andenhanced cardiac arrhythmias. MOA is prolongation of myocardialcell—action potential duration, and refractory period, a 10% increase inQT intervals associated with worsening of arrhythmias and TdP, andnoncompetitive α- and β-adrenergic inhibition. QTc prolongation with andwithout TdP with concomitant administration of fluoroquinolones,macrolide antibiotics or azoles. TEVA Pharmaceuticals IND. Ltd.

Arsenic trioxide: an ineffective hERG blocker (IC₅₀>300 uM), may have anindirect effect on hERG current, an anti-cancer drug. The manufactureris Cephalon, Inc.

Astemizole*: a second generation histamine H1 and H3 receptorantagonist, and antmalarial marketed by Janssen. Structurally similar toterfenidine and haloperidol. Originally used for allergic rhinitis: nolonger available in U.S. because of rare but fatal arrhythmias. IC₅₀ is50 nM hERG tail current.

Bepridil: is a low potency long-acting calcium channel blocking agent(EC50 is 10 uM). Both K+ channels are sensitive targets to calciumchannel blockers. It blocks the rapid component hERG in aconcentration-dependent manner (EC50 is 0.55 uM) and also inhibits theKvLQT1/IsK K+ channel which generates the slow components of the cardiacdelayed rectifier K+ current. These changes can lead to long QT. It isalso a calmodulum antagonist with significant anti-effort associatedangina, and antihypertensive activity. Manufacturer TOCRIS BioscienceInc.

Chloroquine: antimalarial: Novartis Pharma AG. Inhibits hERG channels ina concentration and time manner. The half maximal inhibitoryconcentration (IC₅₀) 2.5 uM.

Chlorpheniramine: a low potency first generation antihistamine H1blocker, which induces QT prolongation, i.e a hERG blocker in aconcentration dependent manner. It affects the channels in the activatedand inactivated states but not in the closed states. Overdose of firstand second generation antihistamines exert arrhythmic effects byaffecting k+ currents.

Chlorpromazine (Thorazine): anti-psychotic/antiemetic/schizophreniadeveloped by Rhone-Poulec in 1950. It causes cardiac arrhythmias (FowlerN O 1976).

Cisapride: used as gastroprokinetic agent by Janssen Inc.: It waswithdrawn in 2000 due to its Long QT side effect (Layton D 2003).

Celaxa (citalopram) a QT prolonger Forest Labs: A selective serotoninreuptake inhibitor (SSRI) which prolongs the QTc interval via directblockade of the potassium hERG channel, disrupts hERG protein expressionin the cell membrane effectively decreasing the number of hERG potassiumchannels and blocks the I-type calcium current leading to prolongeddepolarization. (Witchel et al).

Clarithromycin and Erythromycin: Antibiotics, females are more sensitivethan males. Both cause QT prolongation and TdP. Erythromycin reducteshERG current in a concentration dependent manner with an IC50 of 38.9,and clarithromycin 45.7 uM at clinically relevant concentrations.

Curcumin (diferuloylmethane): Inhibits hERG current(Moha ou Maati H2008). Curcumin at IC50 of 3.5 uM is a moderate potency molecule(Katchman A N, 2005).

Disopyramide: A class 1 antiarrythmic drug (Vaughan WilliamsClassification) associated with acquired LQTS. Prolongs the QT intervaland widens the QRS complex QT in a dose dependent fashion (IC50 7.23uM). Blocks both sodium and potassium channels depresses phase “O”depolarization and prolongs duration of action potential of normalcardiac cells in atrial and ventricular tissues.

Dofetilide: A class III antiarrhythmic agent marked by Pfizer as Tikosynoral capsules used for maintenance of sinus rhythm and atrialfibrillation. Selectively blocks IKr, the delayed rectifier outwardpotassium current. TdP is a serious side effect with a dose relatedincidence of 0.3-10.5%. This is a twofold increase in death risk ifpre-treatment QTc is greater than 479 ms. A high potency hERG blocker:IC50 is 10 nM.

Domperidone: An antidopaminergic drug used as an antinausea agent. ByJanssen Pharmaceuticals, not available in the U.S. Associated withcardiac arrest and arrhythmias, and increased QT prolongations inneonates (Djeddi D 2008).

Doxorubicin: 30 uM prolongs QTc by 13%;causes acute QT prolongationwithout significantly blocking hERG channels but inhibits IKs (IC50:4.78 uM).

Dronedarone: A non-iodinated analogue of amiodarone.(blocks hERG at IC50of 70 nM), used for over 40,000 patients with atrial fibrillation. Wildtype hERG tails measured at −40 mV following activation at +30 mV wereblocked with IC50 values of 59 nM. hERG inhibition followed channelgating, with block developing on membrane depolarization independent ofchannel activation High external [K+] (94 mM) reduced potency of I(hERG)inhibition and is independent of Y652 and F656 aromatic acid residues.Manufactured by Chemsky (Shanghai) International, and Sanofi-Avantis Incas ″Muttag). The UK NIH blocked this drug in 2010 based upon cost.

Droperidol: A central sedative, anti-nausea, anesthesia adjunct,Associated with prolongation of the QT interval, TdP and sudden death.hERG tail currents following test pulses to 50 mV were inhibited with anIC50 of 77.3 nM. hERG channels were affected in their open andinactivated states. Potency was decreased with mutation of Phe-656 tothr or Ser-631 to Ala. Fourteen companies are listed for this compound.

Grepafloxacin: An oral fluoroquinolone antibiotic caused a number ofsevere cardiovascular events including PQTS and was voluntarilywithdrawn from the market. (WHO 1999).

Haldol, Haloperidol: A high potency hERG blocker, antipsychoticschizophrenia, agitation, when given intravenously or at higher thanrecommended doses, risk of sudden death, QT prolongation and TdPincreases. Janssen-Silag Ltd.

Halofantrine: Antimalarial, associated with cardiac arrhythmias andsignificant QT prolongation.females more sensitive than males.Glaxo-Smith-Kline.

Ibutilide: Corvert by Pfizer, a pure class III antiarrythmic for atrialflutter and fibrillation, females more sensitive than males. Inducesslow inward sodium current. Does not block K current, but prolongsaction potential.

Levomethadyl: Opiate agonist/pain control, narcotic dependence. Similarto methadone. Roxanne Labs removed from market because of ventricularrhythm disorders.

Lidoflazine: A piperazine calcium channel blocker with anti-arrhythmicactivity. high potency hERG blocker (IC50 of 16 nM) of the alphasub-unit of the potassium channel. Preferentially inhibits openactivated channels. 13 fold more potent than Verapamil against hERG.

Loratidine, Claritin: A second generation antihistamine, a hERG blockerat an IC50 of 173 nM. may have an indirect effect on hERG repolarizationcurrent. Marked by Schering-Plough.

Lovostatin: A low-potency hERG blocker synthetic.

Mesoridazone: Antipsychotic schizophrenia.

Methadone: Interacts with the voltage-gated myocardial potassiumchannels in a concentration dependent manner causing serious cardiacarrhythmias, and deaths from TdP and ventricular fibrillation inpatients taking methadone. IC50 is 4.8 uM (compared with 427 uM forheroin) an antidopaminergic drug. Methadone related predispositions toTdP are female, high dosages, CYP2 B6 slow metabolizer of S-methadoneand DNA polymorphisms. Parenterol methadone and chlorobutanolcombinations are contraindicated. QT prolonging activity is mainly dueto S-methadone which blocks hERG current 3-5 fold more potently thanR-methadone.

Methanesulphonanilide (E-4031): An extremely high potency compound,inhibits hERG at nM concentrations. Used as positive control in standardassays.

Moxifloxacin: A hERG channel blocker: at 100 uM prolonged QTc by 22% notprevented by dexrazoxane.

Pentamadine: An ineffective hERG blocker(IC50>300 uM), anti-infective,pneumocystis pneumonia. Associated with QT interval lengthening and TdP,hence may have an unknown indirect effect on hERG repolarization.

Pimozide: Antipsychotic, Tourette's tics.

Prenylamine: A moderate hERG blocker.

Probucol: Antilipemic, anticholesterolemic, no longer available in theU.S.

Procainamide: Anti-arrythmic.

Propafenone: A low-potency hERG blocker(IC50>1 uM).

Pyrilamine: A low potency hERG blocker.

Quinidine: Anti-arrythmic females>males.

Seldane (Terfenidine): A high potency hERG blocker.

Sertindole: A moderate potency hERG blocker.

Sotalol: A LQT2 model, action is prevented by nicorandil a potassiumchannel opener. It can act as an antiarrythmic, β-blocker forventricular tachycardia, atrial fibrillation (Ducroq J 2005). Two (2) %of 1288 patients exhibited QT prolongation, and a QTc greater than 455ms lead to TdP.

Sparfloxacin: Antibiotic.

Thioridazine: A moderate potency hERG blocker.

Vandetanib: An oral kinase inhibitor marketed by Astra-Zeneca isapproved for progressive metastatic or locally advanced medullarythyroid cancer. QT prolongation, TdP and sudden death are included in aboxed warning. The most common (>5%) grade ¾ adverse reactions includesQT prolongation fatigue and rash.

Terfenadine an antihistamine prodrug for the active form fexofenadine,and E-4031 were selected as a reference compounds for this study.Terfenadine has reported ventricular arrhythmias cardiotoxic effects,particularly if taken in combination with macrolide antibiotics orketoconazole. An IC50 hERG inhibitory effect value of 99 nM wascalculated from data obtained in the same cell line as that used for thetest article in this study. E-4031, a class III anti-arrhythmic drug isa synthetic toxin used solely for research purposes with one clinicalexception (Okada Y.,1996). Its mechanism of action is to block the hERGvoltage-gated potassium channels. At 100 nM E-4031 inhibited 90.6% ofthe current density. The inhibitions observed are in line with internalvalidation data generated in identical conditions, and agree withpublished inhibition values for this compound. These results confirm thesensitivity of the test system to hERG-selective inhibitors, in thiscase, Terfenadine and E-4031.

The effect of Curcumin on whole-cell IKr hERG currents: whole-cellcurrents elicited during a voltage pulse were recorded in baselineconditions, following the application of the selected concentrations ofcurcumin and following a washout period. As per protocol, 4concentrations of curcumin were analyzed for hERG current inhibition.The cells were depolarized for one second from the holding potential(−80 mV) to a maximum value of +40 mV, starting at −40 mV andprogressing in 10 mV increments. The membrane potential was thenrepolarized to −55 mV for one second, and finally returned to −80 mV.

Whole-cell tail current amplitude was measured at a holding potential of−55 mV, following activation of the current from −40 to +40 mV. Currentamplitude was measured at the maximum (peak) of this tail current.Current density was obtained by dividing current amplitude by cellcapacitance measured prior to capacitive transient minimization.

Current run-down and solvent effect correction: all data points havebeen corrected for solvent effect and time-dependent current run-down.Current run-down and solvent effects were measured simultaneously byapplying the experimental design in test-article free conditions (DMSO)over the same time frame as was done with the test article. The loss incurrent amplitude measured during these so-called vehicle experiments(representing both solvent effects and time-dependent run-down) wassubtracted from the loss of amplitude measured in the presence of thetest article to isolate the effect of the test article, apart from theeffect of the solvent and the inevitable run-down in current amplitudeover time.

The study presented herein quantified the effect of curcumin solubilizedin DMSO on IKr. The concentrations of curcumin (0.014, 0.2, 3.4 and 11.4μM) were based on information available at the time of the design ofthis study. The concentrations were selected based on: (1) the predictedhuman plasma levels at the planned lowest Phase 1 dose level; (2) thepredicted human plasma concentrations at the planned highest Phase 1dose level; (3) 30-fold over the predicted human therapeutic plasmalevels; and (4) 100-fold over the predicted human therapeutic plasmalevels. These selected concentrations are considered to provide valuablepredictions of the effect of curcumin on human cardiacelectrophysiology. Curcumin 99.2% pure, was synthesized under GMPconditions in Sami Labs, Bangalore, India and stored at 4 oC in theabsence of light. One mL aliquot of each curcumin concentration used toexpose the cells included in this study were independently analyzed forcurcumin content. For the subsequent studies GMP grade liposomalcurcumin was formulated at Polymun GmbH, Vienna Austria, and stored at 4oC. The liposomes were obtained from Polymun GmbH, terfenadine andE04031 were purchased from Sigma Aldrich Fine Chemicals.

TABLE 1 Effect of terfenadine, a positive control on hERG currentdensity from transfected HEK 293 cells at 20 mV. Corrected NormalizedNormalized Current Current Density Density SEM p value n= Baseline 1.0001.000  n/a n/a 3 Terfenadine, 0.01 μM* 0.645 0.767  0.090 0.122 3Terfenadine, 0.03 μM** 0.650 0.772  0.073 0.088 3 Terfenadine, 0.1 μM**0.362 0.483* 0.063 0.015 3 *10 nM, **30 nM, ***100 nM.

Terfenadine inhibited IKr with an IC50 of 0.065 umolar (65 nM) potency.

TABLE 2 Effect of Terfenadine on hERG current density from transfectedHEK 293 cells at 20 mV. Corrected Normalized Normalized Current CurrentDensity Density SEM p value n= Baseline 1.000 1.000  n/a n/a 3Terfenadine, 30 nM 0.469 0.548  0.080 0.111 2 Terfenadine, 100 nM 0.3990.478* 0.072 0.018 3 Terfenadine, 300 nM 0.043 0.122* 0.004 0.000 3 *Thecurrent recorded after exposure to the test article concentration wasstatistically different from the current recorded in baseline condition.Difference was considered statistically significant when p ≦ 0.05.

FIG. 1 is a graphical representation of the data presented in Table 2.FIG. 2 is a plot of the current-voltage (I-V) relationship of hERGcurrent amplitude from transfected HEK 293 cells exposed to terfenadine.FIG. 3 is a plot of the effect of terfenadine on hERG current densityfrom transfected HEK 293 cells at 20 mV. FIG. 4 is a plot of the I-Vrelationship of hERG current amplitude from transfected HEK 293 cellsexposed to terfenadine.

TABLE 3 Effect of E-4031 on hERG current density from transfected HEK293 cells at 20 mV. Corrected Normalized Normalized Current CurrentDensity Density SEM p value n= Baseline 1.000 1.000  n/a n/a 3 E-4031,100 nM 0.124 0.094* 0.067 0.0055 3 E-4031 inhibited IKr with an IC50 of50 nM. FIG. 5 is a plot showing the effect of E-4031 on hERG currentdensity from transfected HEK 293 cells at 20 mV.

TABLE 4 Effect of Curcumin on hERG current density from transfected HEK293 cells at 20 mV. Corrected Normalized Normalized Current CurrentDensity Density SEM p value n= Baseline 1.000 1.000  n/a n/a 7 Curcumin,0.014 μM 0.892 0.862  0.084 0.1521 7 Curcumin, 0.2 μM 0.773 0.744* 0.0700.0107 7 Curcumin, 3.4 μM 0.642 0.612* 0.095 0.0064 7 Curcumin, 11.4 μM0.234 0.204* 0.016 0.0000 7 Washout 0.489 0.459  0.127 0.2036 3

At a concentration of 11.4 μM curcumin caused 79.6% inhibition of thehERG tail current density at I+20 (n=7). Paired student's t-testsconfirmed that the difference in normalized current density measured atbaseline and in the presence of 0.2 to 11.4 μM of curcumin reached theselected threshold for statistical significance (p≦0.05). Table 3provides p-values obtained from statistical analysis. Fifty percentinhibition of the current was achieved within the range ofconcentrations (0.014 to 11.4 μM) selected for this study. An IC50 valueof 4.9 μM was calculated from the data obtained. FIG. 6 is a plot ofdata shown in Table 4. FIG. 7 is a plot of the I-V relationship of hERGcurrent amplitude from transfected HEK 293 cells exposed to curcumin.

TABLE 5 Effect of Curcumin (as liposomal curcumin) on hERG currentdensity from transfected HEK 293 cells at 20 mV. Corrected NormalizedNormalized Current Current Density Density SEM p value n= Baseline 1.0001.000  n/a n/a 7 Curcumin 0.854 0.934  0.039 0.142 7 (liposomalcurcumin), (0.014 μM) Curcumin 0.838 0.918  0.092 0.408 7 (liposomalcurcumin), (0.2 μM) Curcumin 0.769 0.848  0.072 0.079 7 (liposomalcurcumin), (3.4 μM) Curcumin 0.716 0.795* 0.082 0.046 7 (liposomalcurcumin), (11.4 μM) Washout 0.474 0.554* 0.101 0.020 4

p-values obtained from statistical analysis indicates borderlinesignificant differences of current density from baseline at 11.4 uM,however the extent of current inhibition was less than the IC50.

FIG. 8 is a plot showing the effect of curcumin (as liposomal curcumin)on hERG current density from transfected HEK 293 cells at 20 mV and FIG.9 is a plot showing the I-V relationship of hERG current amplitude fromtransfected HEK 293 cells exposed to Curcumin (as liposomal curcumin).

In Table 5 the rectifying inward current showed that the inhibitioneffect of curcumin on the hERG tail current is voltage dependent withhigher potency at positive holding potentials. The currents recordedafter washout were compared statistically to the currents recorded afterthe highest concentration of Curcumin (liposomal curcumin) (11.4 μM).

TABLE 6 Effect of empty liposome vortexed with curcumin on hERG currentdensity from transfected HEK 293 cells at 20 mV. Corrected NormalizedNormalized Current Current Density Density SEM p value n= Baseline 1.0001.000 n/a n/a 3 Curcumin (Lipo-Curc.), 0.937 0.994 0.073 0.946 3 0.2 μMCurcumin (Lipo-Curc.), 0.738 0.796 0.055 0.064 3 3.4 μM Curcumin(Lipo-Curc.), 0.498 0.555 0.119 0.064 3 11.4 μM Washout 0.479 0.5360.145 0.899 3

Liposome concentration was 0.7, 12, 41 ng/ml. No significant differencefrom curcumin at any dose level.

FIG. 10 is a plot showing the effect of Curcumin (Liposomes+Curcumin) onhERG current density from transfected HEK 293 cells at 20 mV, and FIG.11 is a plot of the I-V relationship of hERG current amplitude fromtransfected HEK 293 cells exposed to Curcumin (Liposomes+Curcumin). Thecurrent recorded after washout was compared and similar statistically tothe currents recorded after the highest concentration of curcumin at11.4 uM. The current IC50 was not reached.

TABLE 7 Effect of Liposomes on hERG current density from transfected HEK293 cells at 20 mV. Corrected Normalized Normalized Current CurrentDensity Density SEM p value n= Baseline 1.000 1.000 n/a n/a 3 Liposome,0.7227 ng/mL 0.921 1.041 0.037 0.379 3 Liposome, 12.285 ng/mL 0.8050.926 0.065 0.374 3 Liposome, 41.193 ng/mL 0.888 1.009 0.075 0.919 3Washout 0.817 0.938 0.151 0.734 3

Liposomes do not exhibit an inhibitory effect on the in vitro hERGchannel. The current recorded after washout was comparable statisticallyto the currents recorded after the highest concentration of Liposomes(41.193 ng/mL). FIG. 12 is a plot of the data presented in Table 7, andFIG. 13 is a plot of the I-V relationship of hERG current amplitude fromtransfected HEK 293 cells exposed to liposomes.

TABLE 8 Effect of Liposomes + E-4031 on hERG current density fromtransfected HEK 293 cells at 20 mV. Corrected Normalized NormalizedCurrent Current Density Density SEM p value n= Baseline 1.000 1.000  n/an/a 3 Liposome, 0.72 ng/mL + 0.489 0.610  0.115 0.077 3 E-4031, 30 nMLiposome, 12.29 ng/mL + 0.219 0.339* 0.067 0.010 3 E-4031, 100 nMLiposome, 41.19 ng/mL + 0.171 0.292* 0.022 0.001 3 E-4031, 300 nMWashout 0.130 0.251  0.037 0.675 2 *the current recorded after exposureto the test article concentration was statistically different p ≦ 0.05from the current recorded in baseline condition.

FIG. 14 is a plot showing the effect of liposomes+E-4031 on hERG currentdensity from transfected HEK 293 cells at 20 mV. FIG. 15 is a plot ofthe I-V relationship of hERG current amplitude from transfected HEK 293cells exposed to Liposomes+E-4031.

Empty Liposomes when vortexed with E-4031 at 30-300 nM concentrations donot prohibit the anti-hERG effect of E-4031. E-4031 inhibition. Thecurrent recorded after washout was compared statistically to thecurrents recorded after the highest concentration of Liposomes+E-4031.

TABLE 9 Effect of Liposomes + Terfenadine on hERG current density fromtransfected HEK 293 cells at 20 mV. Corrected Normalized NormalizedCurrent Current Density Density SEM p value n= Baseline 1.000 1.000  n/an/a 3 Terfenadine (Liposome + 0.298 0.392* 0.065 0.011 3 Terfenadine),30 nM Terfenadine (Liposome + 0.122 0.216* 0.073 0.008 3 Terfenadine),100 nM Terfenadine (Liposome + 0.117 0.211* 0.032 0.000 4 Terfenadine),300 nM Washout 0.276 0.369  0.017 0.081 2 *Mean that the currentrecorded after exposure to the test article concentration wasstatisticallydifferent from the current recorded in baseline condition.Difference was considered statistically significant when p ≦ 0.05.

The data presented in Table 9 hereinabove is represented graphically inFIG. 16 and FIG. 17 is a plot showing the I-V relationship of hERGcurrent amplitude from transfected HEK 293 cells exposed toliposomes+terfenadine. There was no effect of empty liposones whenvortexed with Terfenadine at 30-300 nM the Terfenadine inhibition ofhERG current density.

The data presented hereinabove suggest that curcumin, within the rangeof concentrations tested and in the specific context of this studydown-modulates the IKr current, i.e., it interacts with the proteinsencoded by the hERG gene and activates channel gating functionsdecreasing ion flow. A similar observation with a curcuminoid mixture(78% curcumin) was published (Moha ou Matti, 2008). These data supporttheir initial observation, and emphasize that the curcumin(diferuloylmethane) molecule exhibits the predominant if not all the IKrinhibition.

The findings of the present invention that liposomal curcumin orvortexed mixtures of liposomes with curcumin prohibited IKr downmodulation by curcumin allowing normal gating functions to occur suggestthat liposome encapsulation of curcumin is not necessary to preventinteractions with channel drug receptor sites. The empty liposome didnot appear to interact with the protein encoded by the hERG gene in theabsence of curcumin, or in the presence of E-4031 and terfenadinerelates to questions regarding the specificity and degree of affinitiesor preferential interactions of the receptors in the K+ channel(Zachariae U 2009).

Ikr/hERG suppression induced by curcumin is mitigated when the curcuminis incorporated within a liposome or simply vortexed with it prior toexposure. Combined intravenous administration of this liposome andintravenous QT prolonging drugs other than curcumin may mitigate delayedQT in vivo.

It is contemplated that any embodiment discussed in this specificationcan be implemented with respect to any method, kit, reagent, orcomposition of the invention, and vice versa. Furthermore, compositionsof the invention can be used to achieve methods of the invention.

It will be understood that particular embodiments described herein areshown by way of illustration and not as limitations of the invention.The principal features of this invention can be employed in variousembodiments without departing from the scope of the invention. Thoseskilled in the art will recognize, or be able to ascertain using no morethan routine experimentation, numerous equivalents to the specificprocedures described herein. Such equivalents are considered to bewithin the scope of this invention and are covered by the claims.

All publications and patent applications mentioned in the specificationare indicative of the level of skill of those skilled in the art towhich this invention pertains. All publications and patent applicationsare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

The use of the word “a” or “an” when used in conjunction with the term“comprising” in the claims and/or the specification may mean “one,” butit is also consistent with the meaning of “one or more,” “at least one,”and “one or more than one.” The use of the term “or” in the claims isused to mean “and/or” unless explicitly indicated to refer toalternatives only or the alternatives are mutually exclusive, althoughthe disclosure supports a definition that refers to only alternativesand “and/or.” Throughout this application, the term “about” is used toindicate that a value includes the inherent variation of error for thedevice, the method being employed to determine the value, or thevariation that exists among the study subjects.

As used in this specification and claim(s), the words “comprising” (andany form of comprising, such as “comprise” and “comprises”), “having”(and any form of having, such as “have” and “has”), “including” (and anyform of including, such as “includes” and “include”) or “containing”(and any form of containing, such as “contains” and “contain”) areinclusive or open-ended and do not exclude additional, unrecitedelements or method steps.

The term “or combinations thereof” as used herein refers to allpermutations and combinations of the listed items preceding the term.For example, “A, B, C, or combinations thereof” is intended to includeat least one of: A, B, C, AB, AC, BC, or ABC, and if order is importantin a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB.Continuing with this example, expressly included are combinations thatcontain repeats of one or more item or term, such as BB, AAA, MB, BBC,AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan willunderstand that typically there is no limit on the number of items orterms in any combination, unless otherwise apparent from the context.

All of the compositions and/or methods disclosed and claimed herein canbe made and executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of this inventionhave been described in terms of preferred embodiments, it will beapparent to those of skill in the art that variations may be applied tothe compositions and/or methods and in the steps or in the sequence ofsteps of the method described herein without departing from the concept,spirit and scope of the invention. All such similar substitutes andmodifications apparent to those skilled in the art are deemed to bewithin the spirit, scope and concept of the invention as defined by theappended claims.

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Etheridge S P. Compton S J, Tristani-Firouzi M, Mason J W: A new oraltherapy for long QT syndrome: long term oral potassium improvesrepolarization in patients with hERG mutations. J AM Coll Cardiol 200342:1777-1782.

Fauchier L, Babuty D Poret P, Autret M L, Cosnay P, Fauchier J P: Effectof Verapamil on QT interval dynamicity. AM J Cardiol. 1999 83(5):807-808A10-1.

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What is claimed is:
 1. A composition for preventing one or more cardiacchannelopathies, conditions resulting from irregularities or alterationsin cardiac patterns, or both in a human or animal subject comprising:one or more pharmacologically active agents selected from one or moredrug classes comprising β-blockers, sodium channel blockers, potassiumsupplements, potassium channel openers, hERG current enhancers, calciumchannel blockers, agents for correcting trafficking defects, gapjunction coupling enhancers, or any combinations thereof; one or moreliposomes, wherein the liposomes are empty liposomes and administeredprior to, concomitantly, or after administration of thepharmacologically active agent; and an optional pharmaceuticallyacceptable dispersion medium, solvent, or vehicle, wherein the activeagent, the liposome or both are dissolved, dispersed, or suspended inthe medium, the solvent, or the vehicle.
 2. The composition of claim 1,wherein the cardiac channelopathy or the condition resulting from theirregularity or alteration in the cardiac pattern is selected from thegroup consisting of long QT syndrome (LQTS), atrial flutter, atrialfibrillation, ventricular tachycardia, sinus bradycardia, sinustachycardia, atrial tachycardia, atrial fibrillation, atrial flutter,atrioventricular nodal block, atrioventricular node reentry tachycardia,atrioventricular reciprocating tachycardia, ventricular tachycardia,ventricular fibrillation, or any combinations thereof.
 3. Thecomposition of claim 1, wherein the cardiac condition is LQTS.
 4. Thecomposition of claim 3, wherein the LQTS is a drug-induced condition, agenetic condition, or both.
 5. The composition of claim 1, wherein thecomposition is used for the treatment or prevention of LQTS induced byadministration of one or more drugs used in the treatment of cardiac ornon-cardiac related diseases.
 6. The composition of claim 5, wherein theone or more drugs comprise Aloxi or palonasitron HCL, Amiodarone,Arsenic trioxide, Astemizole, Bepridil, Chloroquine-Chlorpheniramine,Chlorpromazine, Cisapride, Celaxa, Clarithromycin, Erythromycin,Curcumin, Disopyramide, Dofetilide, Domperidone, Doxorubicin,Dronedarone, Droperidol, Grepafloxacin, Haldol, Haloperidol,Halofantrine, Ibutilide, Levomethadyl, Lidoflazine, Loratidine,Lovostatin, Mesoridazone, Methadone, Methanesulphonanilide (E-4031),Moxifloxacin, Pentamadine, Pimozide, Prenylamine, Probucol,Procainamide, Propafenone, Pyrilamine, Quinidine- Terfenidine,Sertindole, Sotalol, Sparfloxacin, or Thioridazine.
 7. The compositionof claim 1, wherein the composition is adapted for parenteral or oraladministration.
 8. The composition of claim 1, wherein the active agentand the liposomes may be bound or conjugated together.
 9. Thecomposition of claim 1, wherein the liposomes comprise anionic,cationic, or neutral liposomes.
 10. The composition of claim 1, whereinthe liposomes comprises a lipid or a phospholipid wall, wherein thelipids or the phospholipids are selected from the group consisting ofphosphatidylcholine (lecithin), lysolecithin,lysophosphatidylethanol-amine, phosphatidylserine, phosphatidylinositol,sphingomyelin, phosphatidylethanolamine (cephalin), cardiolipin,phosphatidic acid, cerebrosides, dicetylphosphate, phosphatidylcholine,and dipalmitoyl-phosphatidylglycerol, stearylamine, dodecylamine,hexadecyl-amine, acetyl palmitate, glycerol ricinoleate, hexadecylsterate, isopropyl myristate, amphoteric acrylic polymers, fatty acid,fatty acid amides, cholesterol, cholesterol ester, diacylglycerol, anddiacylglycerol succinate.
 11. The composition of claim 1, wherein theliposomes are spherical liposomes with a diameter ranging from 10 nm-200nm.
 12. A composition for preventing or treating one or more adversereactions arising from administration of a therapeutically active agentor a drug in a human or animal subject comprising: one or moreliposomes, wherein the liposomes are empty liposomes and administeredprior to, concomitantly, or after administration of the therapeuticallyactive agent or the drug; and an optional pharmaceutically acceptabledispersion medium, solvent, or vehicle, wherein the active agent, theliposome or both are dissolved, dispersed, or suspended in the medium,the solvent, or the vehicle.
 13. The composition of claim 12, whereinthe therapeutically active agent or a drug is used in a prevention or atreatment of one or more cardiac or non-cardiac diseases in the human oranimal subject.
 14. The composition of claim 12, wherein the one or moreadverse reactions comprise one or more cardiac channelopathies,irregularities or alterations in cardiac patterns, or both.
 15. Thecomposition of claim 14, the cardiac channelopathy or the irregularityor alteration in the cardiac pattern, or both are selected from thegroup consisting of long QT syndrome (LQTS), atrial flutter, atrialfibrillation, ventricular tachycardia, sinus bradycardia, sinustachycardia, atrial tachycardia, atrial fibrillation, atrial flutter,atrioventricular nodal block, atrioventricular node reentry tachycardia,atrioventricular reciprocating tachycardia, ventricular tachycardia,ventricular fibrillation, or any combinations thereof.
 16. Thecomposition of claim 12, wherein the therapeutically active agent or adrug is selected from one or more drug classes comprising β-blockers,sodium channel blockers, potassium supplements, potassium channelopeners, hERG current enhancers, calcium channel blockers, agents forcorrecting trafficking defects, gap junction coupling enhancers, or anycombinations thereof.
 17. The composition of claim 12, wherein thetherapeutically active agent or the drug comprises Aloxi or palonasitronHCL, Amiodarone, Arsenic trioxide, Astemizole, Bepridil,Chloroquine-Chlorpheniramine, Chlorpromazine, Cisapride, Celaxa,Clarithromycin, Erythromycin, Curcumin, Disopyramide, Dofetilide,Domperidone, Doxorubicin, Dronedarone, Droperidol, Grepafloxacin,Haldol, Haloperidol, Halofantrine, Ibutilide, Levomethadyl, Lidoflazine,Loratidine, Lovostatin, Mesoridazone, Methadone, Methanesulphonanilide(E-4031), Moxifloxacin, Pentamadine, Pimozide, Prenylamine, Probucol,Procainamide, Propafenone, Pyrilamine, Quinidine- Terfenidine,Sertindole, Sotalol, Sparfloxacin, or Thioridazine.
 18. The compositionof claim 12, wherein the adverse reaction is LQTS.
 19. The compositionof claim 12, wherein the composition is adapted for parenteral or oraladministration.
 20. The composition of claim 12, wherein the liposomescomprise anionic, cationic, or neutral liposomes comprising a lipid or aphospholipid wall, wherein the lipids or the phospholipids are selectedfrom the group consisting of phosphatidylcholine (lecithin),lysolecithin, lysophosphatidylethanol-amine, phosphatidylserine,phosphatidylinositol, sphingomyelin, phosphatidylethanolamine(cephalin), cardiolipin, phosphatidic acid, cerebrosides,dicetylphosphate, phosphatidylcholine, anddipalmitoyl-phosphatidylglycerol, stearylamine, dodecylamine,hexadecyl-amine, acetyl palmitate, glycerol ricinoleate, hexadecylsterate, isopropyl myristate, amphoteric acrylic polymers, fatty acid,fatty acid amides, cholesterol, cholesterol ester, diacylglycerol, anddiacylglycerol succinate.
 21. A method for preventing or treating one ormore cardiac channelopathies, irregularities or alterations in cardiacpatterns, or both in a human or animal subject comprising the steps of:identifying the human or animal subject in need of prevention ortreatment of the one or more cardiac channelopathies, irregularities oralterations in cardiac patterns, or both; and administering to the humanor animal subject a therapeutically effective amount of a compositioncomprising: one or more pharmacologically active agents selected fromone or more drug classes comprising β-blockers, sodium channel blockers,potassium supplements, potassium channel openers, hERG currentenhancers, calcium channel blockers, agents for correcting traffickingdefects, gap junction coupling enhancers, or any combinations thereof;one or more liposomes, wherein the liposomes are empty liposomes andadministered prior to, concomitantly, or after administration of thepharmacologically active agent; and an optional pharmaceuticallyacceptable dispersion medium, solvent, or vehicle, wherein the activeagent, the liposome or both are dissolved, dispersed, or suspended inthe medium, the solvent, or the vehicle.
 22. The method of claim 21,wherein the cardiac channelopathy or the condition resulting from theirregularity or alteration in the cardiac pattern is selected from thegroup consisting of long QT syndrome (LQTS), atrial flutter, atrialfibrillation, ventricular tachycardia, sinus bradycardia, sinustachycardia, atrial tachycardia, atrial fibrillation, atrial flutter,atrioventricular nodal block, atrioventricular node reentry tachycardia,atrioventricular reciprocating tachycardia, ventricular tachycardia,ventricular fibrillation, or any combinations thereof.
 23. The method ofclaim 21, wherein the cardiac condition is LQTS.
 24. The method of claim23, wherein the LQTS is a drug-induced condition, a genetic condition,or both.
 25. The method of claim 21, wherein the composition treats orprevents LQTS induced by administration of one or more drugs used in thetreatment of cardiac or non-cardiac related diseases.
 26. The method ofclaim 25, wherein the one or more drugs comprise Aloxi or palonasitronHCL, Amiodarone, Arsenic trioxide, Astemizole, Bepridil,Chloroquine-Chlorpheniramine, Chlorpromazine, Cisapride, Celaxa,Clarithromycin, Erythromycin, Curcumin, Disopyramide, Dofetilide,Domperidone, Doxorubicin, Dronedarone, Droperidol, Grepafloxacin,Haldol, Haloperidol, Halofantrine, Ibutilide, Levomethadyl, Lidoflazine,Loratidine, Lovostatin, Mesoridazone, Methadone, Methanesulphonanilide(E-4031), Moxifloxacin, Pentamadine, Pimozide, Prenylamine, Probucol,Procainamide, Propafenone, Pyrilamine, Quinidine- Terfenidine,Sertindole, Sotalol, Sparfloxacin, and Thioridazine.
 27. A method forpreventing or treating one or more adverse reactions arising fromadministration of a therapeutically active agent or a drug in a human oranimal subject comprising the steps of: identifying the human or animalsubject in need of prevention or treatment of the one or more adversereactions arising from the administration of the therapeutically activeagent or the drug; and administering to the human or animal subject atherapeutically effective amount of a composition comprising: one ormore liposomes, wherein the liposomes are empty liposomes andadministered prior to, concomitantly, or after administration of thetherapeutically active agent or the drug; and an optionalpharmaceutically acceptable dispersion medium, solvent, or vehicle,wherein the active agent, the liposome or both are dissolved, dispersed,or suspended in the medium, the solvent, or the vehicle.
 28. Acomposition for preventing or treating long QT syndrome (LQTS) arisingfrom administration of Terfenidine, Methanesulphonanilide (E-4031), orany other active agent for treatment of a cardiac condition or a diseasein a human or animal subject comprising: one or more liposomes, whereinthe liposomes are empty liposomes and administered prior to,concomitantly, or after administration of the Terfenidine,Methanesulphonanilide (E-4031), or any other active agent; and anoptional pharmaceutically acceptable dispersion medium, solvent, orvehicle, wherein the Terfenidine, Methanesulphonanilide (E-4031), or theany other active agent, the liposome or both are dissolved, dispersed,or suspended in the medium, the solvent, or the vehicle.
 29. A methodfor preventing or treating long QT syndrome (LQTS) arising fromadministration of Terfenidine, Methanesulphonanilide (E-4031), or anyother active agent for treatment of a cardiac condition or a disease ina human or animal subject comprising the steps of: identifying the humanor animal subject in need of prevention or treatment of the LQTS arisingfrom the administration of Terfenidine, Methanesulphonanilide (E-4031),or any other active agent; and administering to the human or animalsubject a therapeutically effective amount of a composition comprising:one or more liposomes, wherein the liposomes are empty liposomes andadministered prior to, concomitantly, or after administration of theTerfenidine, Methanesulphonanilide (E-4031), or any other active agent;and an optional pharmaceutically acceptable dispersion medium, solvent,or vehicle, wherein the Terfenidine, Methanesulphonanilide (E-4031), orthe any other active agent, the liposome or both are dissolved,dispersed, or suspended in the medium, the solvent, or the vehicle.